EP3218356B1 - Compositions anti-hcmv et procédés - Google Patents
Compositions anti-hcmv et procédés Download PDFInfo
- Publication number
- EP3218356B1 EP3218356B1 EP15859834.2A EP15859834A EP3218356B1 EP 3218356 B1 EP3218356 B1 EP 3218356B1 EP 15859834 A EP15859834 A EP 15859834A EP 3218356 B1 EP3218356 B1 EP 3218356B1
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- European Patent Office
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- compound
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- 238000000034 method Methods 0.000 title claims description 103
- 239000000203 mixture Substances 0.000 title description 100
- 150000001875 compounds Chemical class 0.000 claims description 283
- 125000004432 carbon atom Chemical group C* 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- -1 rimantidine Chemical compound 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 25
- 206010011831 Cytomegalovirus infection Diseases 0.000 claims description 24
- 241000701024 Human betaherpesvirus 5 Species 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 10
- 239000003443 antiviral agent Substances 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 6
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 6
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims description 4
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 claims description 4
- 229960002963 ganciclovir Drugs 0.000 claims description 4
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 claims description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 4
- 229960003752 oseltamivir Drugs 0.000 claims description 4
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 claims description 4
- 229960002555 zidovudine Drugs 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- CNPVJJQCETWNEU-CYFREDJKSA-N (4,6-dimethyl-5-pyrimidinyl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methyl-1-piperazinyl]-4-methyl-1-piperidinyl]methanone Chemical compound N([C@@H](COC)C=1C=CC(=CC=1)C(F)(F)F)([C@H](C1)C)CCN1C(CC1)(C)CCN1C(=O)C1=C(C)N=CN=C1C CNPVJJQCETWNEU-CYFREDJKSA-N 0.000 claims description 2
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 2
- YLDCUKJMEKGGFI-QCSRICIXSA-N 4-acetamidobenzoic acid;9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one;1-(dimethylamino)propan-2-ol Chemical compound CC(O)CN(C)C.CC(O)CN(C)C.CC(O)CN(C)C.CC(=O)NC1=CC=C(C(O)=O)C=C1.CC(=O)NC1=CC=C(C(O)=O)C=C1.CC(=O)NC1=CC=C(C(O)=O)C=C1.O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC=NC2=O)=C2N=C1 YLDCUKJMEKGGFI-QCSRICIXSA-N 0.000 claims description 2
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 claims description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 claims description 2
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 claims description 2
- 102000053642 Catalytic RNA Human genes 0.000 claims description 2
- 108090000994 Catalytic RNA Proteins 0.000 claims description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 claims description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 claims description 2
- 108010032976 Enfuvirtide Proteins 0.000 claims description 2
- 229940124897 Gardasil Drugs 0.000 claims description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims description 2
- 229930010555 Inosine Natural products 0.000 claims description 2
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 claims description 2
- KJHOZAZQWVKILO-UHFFFAOYSA-N N-(diaminomethylidene)-4-morpholinecarboximidamide Chemical compound NC(N)=NC(=N)N1CCOCC1 KJHOZAZQWVKILO-UHFFFAOYSA-N 0.000 claims description 2
- 108091034117 Oligonucleotide Proteins 0.000 claims description 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims description 2
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims description 2
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 claims description 2
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 claims description 2
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 claims description 2
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 claims description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 2
- SCTJKHUUZLXJIP-RUZDIDTESA-N [(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(=O)OCCCOCCCCCCCCCCCCCCCC)C=NC2=C1N SCTJKHUUZLXJIP-RUZDIDTESA-N 0.000 claims description 2
- WXJFKKQWPMNTIM-VWLOTQADSA-N [(2s)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid Chemical compound CCCCCCCCCCCCCCCCOCCCOP(O)(=O)CO[C@H](CO)CN1C=CC(N)=NC1=O WXJFKKQWPMNTIM-VWLOTQADSA-N 0.000 claims description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 2
- GLWHPRRGGYLLRV-XLPZGREQSA-N [[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 GLWHPRRGGYLLRV-XLPZGREQSA-N 0.000 claims description 2
- 229960004748 abacavir Drugs 0.000 claims description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 2
- 229960004150 aciclovir Drugs 0.000 claims description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 2
- 229960001997 adefovir Drugs 0.000 claims description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 2
- 229960003805 amantadine Drugs 0.000 claims description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 2
- 229960001830 amprenavir Drugs 0.000 claims description 2
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 claims description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 claims description 2
- 229960003277 atazanavir Drugs 0.000 claims description 2
- 229940068561 atripla Drugs 0.000 claims description 2
- 229950005107 brincidofovir Drugs 0.000 claims description 2
- 229960001169 brivudine Drugs 0.000 claims description 2
- 235000010418 carrageenan Nutrition 0.000 claims description 2
- 239000000679 carrageenan Substances 0.000 claims description 2
- 229920001525 carrageenan Polymers 0.000 claims description 2
- 229940113118 carrageenan Drugs 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 229960000724 cidofovir Drugs 0.000 claims description 2
- 229940014461 combivir Drugs 0.000 claims description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 2
- 229960000735 docosanol Drugs 0.000 claims description 2
- 229960002030 edoxudine Drugs 0.000 claims description 2
- XACKNLSZYYIACO-DJLDLDEBSA-N edoxudine Chemical compound O=C1NC(=O)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XACKNLSZYYIACO-DJLDLDEBSA-N 0.000 claims description 2
- 229960003804 efavirenz Drugs 0.000 claims description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 claims description 2
- 229960000366 emtricitabine Drugs 0.000 claims description 2
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 claims description 2
- 229960002062 enfuvirtide Drugs 0.000 claims description 2
- 229960000980 entecavir Drugs 0.000 claims description 2
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 claims description 2
- 229960004396 famciclovir Drugs 0.000 claims description 2
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 2
- 229950008454 favipiravir Drugs 0.000 claims description 2
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 claims description 2
- 229960001447 fomivirsen Drugs 0.000 claims description 2
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- 229960003540 oxyquinoline Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 150000003672 ureas Chemical group 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This document relates to compounds useful for preventing, treating or ameliorating human cytomegalovirus infection.
- HCMV Human cytomegalovirus
- Organ transplant patients under immunosuppressive therapy are at high risk for viral infections; activation of a latent virus as well as donor or community acquired primary infections can cause significant complications including graft rejection, morbidity, and mortality.
- Herpesviruses e.g. HCMV, HSV-1
- polyomaviruses e.g. BKV and JCV
- hepatitis viruses HBV and HCV
- respiratory viruses e.g. influenza A, adenovirus
- Cytomegalovirus is the most prevalent post-transplant pathogen; HCMV can infect most organs, and despite the availability of HCMV antivirals such as ganciclovir, nephrotoxic side effects and increasing rates of drug-resistance significantly reduce graft and patient survival.
- HCMV-mediated immune modulation can reactivate distinct latent viruses carried by most adults.
- WO 03/049702 A2 discloses compounds for the treatment of various diseases, including herpes simplex.
- WO 99/32450 A1 discloses 4-hydroxyquinoline-3-carboxamide and hydrazide compounds that are used to treat or prevent herpes viral infections, in particular human cytomegaloviral infection.
- US2015335657 discloses compounds useful for modulating sirtuin enzymes and as broad spectrum antiviral agents. It discloses the compound
- the invention provides compounds selected from the group consisting of: and pharmaceutically acceptable salts thereof.
- the invention also pertains to pharmaceutical compositions comprising a compound selected from the group consisting of: and a pharmaceutically acceptable carrier.
- the invention relates to a compound selected from the group consisting of: for use as a medicament.
- the compounds of the invention are useful for treating and/or preventing HCMV infections. Any references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method of treatment of the human (or animal) body by therapy (or diagnosis).
- HCMV infections Provided herein are compounds useful in the treatment and/or prevention of HCMV infections.
- the methods include administering a therapeutically effective amount of one or more of the compounds provided herein.
- the compounds provided herein can inhibit HCMV production in a cell infected with the virus. In such embodiments, the cell is contacted with a virus production inhibiting amount of one or more compounds provided herein.
- Ar is selected from the group consisting of: substituted with 0, 1 or 2 groups independently selected from halo, -CN, straight chain or branched alkyl having from 1 to 6 carbon atoms and wherein: R 9 is selected from H, straight chain or branched alkyl having from 1 to 6 carbon atoms, -C(O)R 10 or -SO 2 R 10 and R 10 is selected from straight chain or branched alkyl having from 1 to 6 carbon atoms.
- Some embodiments of the compounds for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein Ar is selected from the group consisting of: wherein:
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein at least one of R 3 , R 4 , or R 5 is in the ortho position and selected from the group consisting of halo, -CN, a straight chain or branched alkyl of 1 to 4 carbon atoms, and a straight or branched alkoxy of 1 to 4 carbon atoms.
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein at least one of R 3 , R 4 , or R 5 is in the ortho position and selected from the group consisting of halo, -CN, and a straight or branched alkoxy of 1 to 4 carbon atoms.
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein at least one of R 3 , R 4 , or R 5 is in the ortho position and selected from the group consisting of halo, -CN, a straight chain or branched alkyl of 1 to 4 carbon atoms, and a straight or branched alkoxy of 1 to 4 carbon atoms, and R 2 is selected from halo, straight chain or branched alkyl having from 1 to 6 carbon atoms, and OR 6 .
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein at least one of R 3 , R 4 , or R 5 is in the ortho position and selected from the group consisting of chloro, methyl, and methoxy.
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein at least one of R 3 , R 4 , or R 5 is in the ortho position and selected from the group consisting of chloro, bromo, and methoxy.
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein at least one of R 3 , R 4 , or R 5 is in the ortho position and selected from the group consisting of chloro, methyl, and methoxy, and R 2 is selected from halo, straight chain or branched alkyl having from 1 to 6 carbon atoms, and OR 6 .
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein at least two of R 3 , R 4 , or R 5 are in the ortho position and selected from the group consisting of halo, -CN, a straight chain or branched alkyl of 1 to 4 carbon atoms, and a straight or branched alkoxy of 1 to 4 carbon atoms.
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein at least two of R 3 , R 4 , or R 5 are in the ortho position and selected from the group consisting of halo, -CN, a straight chain or branched alkyl of 1 to 4 carbon atoms, and a straight or branched alkoxy of 1 to 4 carbon atoms, and R 2 is selected from halo, straight chain or branched alkyl having from 1 to 6 carbon atoms, and OR 6 .
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein two of R 3 , R 4 , or R 5 are chloro in the ortho position.
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein two of R 3 , R 4 , or R 5 are chloro in the ortho position and R 2 is selected from halo, straight chain or branched alkyl having from 1 to 6 carbon atoms, and OR 6 .
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein R 2 is selected from halo, straight chain or branched alkyl having from 1 to 6 carbon atoms, and OR 6 .
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound having the structure of Formula I, wherein when m is 0, n is not 0.
- Some embodiments of the compound for use in a method for treating or preventing an HCMV infection in a subject provided herein can include administering a therapeutically effective amount of a compound selected from the group consisting of: and pharmaceutically acceptable salts thereof.
- Also provided herein are compounds for use in a method of inhibiting HCMV production comprising contacting an HCMV-infected cell with a virus production inhibiting amount of any of the compounds of Formula I.
- an antiviral agent can also be administered in conjunction with the compounds and the methods described herein.
- the agent can be any therapeutic agent useful in the treatment of an HCMV infection.
- an antiviral agent can include acyclovir, docosanol, ribarivin, interferons, and the like; cellulose acetate, carbopol and carrageenan, pleconaril, amantidine, rimantidine, fomivirsen, zidovudine, lamivudine, zanamivir, oseltamivir, brivudine, abacavir, adefovir, amprenavir, arbidol, atazanavir, atripla, cidofovir, combivir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfonet, ganciclo
- a compound provided herein can be administered before, after, or simultaneously with the administration or one or more antiviral agents.
- a compound provided herein, including a pharmaceutically acceptable salt thereof, can be purchased commercially or prepared using known organic synthesis techniques.
- compositions which include compounds provided herein and one or more pharmaceutically acceptable carriers. Also provided herein are the compositions themselves.
- compositions typically include a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
- a pharmaceutical composition is typically formulated to be compatible with its intended route of administration.
- routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
- solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- the parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.
- compositions suitable for injection can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
- the composition must be sterile and should be fluid to the extent that easy syringability exists.
- the composition should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions can be prepared by incorporating a compound provided herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating a compound provided herein into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of a compound provided herein plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Oral compositions generally include an inert diluent or an edible carrier.
- a compound provided herein can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules.
- Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.
- Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
- a lubricant such as magnesium stearate or Sterotes
- a glidant such as colloidal silicon dioxide
- the compounds can be delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
- a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
- Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the compounds provided herein can be formulated into ointments, salves, gels, or creams as generally known in the art.
- compositions can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
- suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
- retention enemas for rectal delivery.
- intranasal delivery is possible, as described in, inter alia, Hamajima et al., Clin. Immunol. Immunopathol., 88(2), 205-10 (1998 ).
- Liposomes e.g., as described in U.S. Patent No. 6,472,375
- microencapsulation can also be used.
- Biodegradable targetable microparticle delivery systems can also be used (e.g., as described in U.S. Patent No. 6,471,996 ).
- the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
- a controlled release formulation including implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
- Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc.
- Liposomal suspensions (including liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 .
- the pharmaceutical composition may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
- compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. Methods for preparation of these compositions are known to those skilled in the art.
- the contemplated compositions may contain 0.001%-100% of a compound provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%.
- compositions can be included in a container, pack, or dispenser together with instructions for administration.
- the preparations of one or more compounds provided herein may be given orally, parenterally, topically, or rectally. They are, of course, given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, infusion; topically by lotion or ointment; and rectally by suppositories. In some embodiments, administration is oral.
- parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection, and infusion.
- Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
- compositions provided herein can be provided in an aqueous solution containing about 0.1-10% w/v of a compound disclosed herein, among other substances, for parenteral administration. Typical dose ranges can include from about 0.01 to about 50 mg/kg of body weight per day, given in 1-4 divided doses. Each divided dose may contain the same or different compounds.
- the dosage will be a therapeutically effective amount depending on several factors including the overall health of a patient, and the formulation and route of administration of the selected compound(s).
- a daily dosage of from 0.01 to 2000 mg of the compound is recommended for an adult human patient, and this may be administered in a single dose or in divided doses.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
- the precise time of administration and/or amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), route of administration, etc.
- physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication
- route of administration etc.
- the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the patient and adjusting the dosage and/or timing.
- conjoint therapy wherein one or more other therapeutic agents are administered with a compound or a pharmaceutical composition comprising a compound provided herein.
- Such conjoint treatment may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment.
- a "subject,” as used herein, includes both humans and other animals, particularly mammals. Thus, the methods are applicable to both human therapy and veterinary applications.
- the patient is a mammal, for example, a primate. In some embodiments, the patient is a human.
- a “therapeutically effective” amount of a compound provided herein is typically one which is sufficient to prevent, eliminate, ameliorate or reduce the symptoms of an HCMV infection. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease.
- a “virus production inhibiting" amount of a compound provided herein is typically one which is sufficient to achieve a measurable reduction in the amount of virus produced by the cells contacted with the compound.
- a “virus production inhibiting” amount is an amount which inhibits a least 30% of the virus production in untreated cells.
- a “virus production inhibiting” amount is an amount which inhibits a least 50% of the virus production in untreated cells.
- a “virus production inhibiting” amount is an amount which inhibits a least 70% of the virus production in untreated cells.
- a “virus production inhibiting” amount is an amount which inhibits a least 90% of the virus production in untreated cells.
- treatment and “prevention” are art-recognized and include administration of one or more of the compounds or pharmaceutical compositions provided herein. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is preventative, (i.e., it protects the subject against developing the unwanted condition).
- prevent means to slow or prevent the onset of at least one symptom of a disorder as provided herein. For example, such prevention may be prompted by a likelihood of exposure to an infective agent (e.g., a virus) or when a subject exhibits other symptoms that indicate onset of a disorder (e.g., a metabolic disorder or cardiovascular disorder) may be likely.
- the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
- to "treat” means to ameliorate at least one symptom of a disorder as provided herein.
- a compound provided herein, or salt thereof is substantially isolated.
- substantially isolated it is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
- Partial separation can include, for example, a composition enriched in the compound provided herein.
- Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
- phrases "pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid addition salts of a compound provided herein. These salts can be prepared in situ during the final isolation and purification of a compound provided herein, or by separately reacting the compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
- Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like.
- sulfate bisulfate
- phosphate nitrate
- acetate valerate
- oleate palmitate
- stearate laurate
- benzoate lactate
- phosphate tosylate
- citrate maleate
- fumarate succinate
- tartrate naphthylate
- mesylate glucoheptonate
- lactobionate lactobionate
- laurylsulphonate salts
- a compound provided herein may contain one or more acidic functional groups and, thus, is capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
- pharmaceutically acceptable salts refers to the relatively non-toxic inorganic and organic base addition salts of a compound provided herein. These salts can likewise be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
- Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
- Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).
- alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents.
- Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, pentyl, and hexyl.
- a "Co” alkyl (as in "C 0 -C 3 -alkyl”) is a covalent bond (like "Co” hydrocarbyl).
- lower alkyl refers to straight and branched chain aliphatic groups having from 1 to 6 carbon atoms. Unless otherwise specified, the term “alkyl” includes alkenyl, alkynyl and cyclic alkyl groups.
- alkenyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents.
- Preferred alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
- alkynyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents.
- Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
- heteroalkyl refers to an alkyl group, as defined herein above, wherein one or more carbon atoms in the chain are replaced by a heteratom selected from the group consisting of O, S, and N.
- aryl is a C 6 -C 14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted.
- the aryl group is a C 6 -C 10 aryl group.
- Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
- a “heterocyclyl” or “heterocyclic” group is a ring structure having from about 3 to about 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S.
- the heterocyclic group is optionally substituted on carbon at one or more positions.
- the heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl.
- heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino.
- the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocyles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms.
- heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S.
- a “heteroaralkyl” or “heteroarylalkyl” group comprises a heteroaryl group covalently linked to an alkyl group, either of which is independently optionally substituted or unsubstituted.
- Preferred heteroalkyl groups comprise a C1-C6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms.
- Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms.
- Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl.
- Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms.
- heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolen
- a moiety e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.
- a moiety e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.
- the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.
- Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
- halogen refers to chlorine, bromine, fluorine, or iodine.
- acyl refers to an alkylcarbonyl or arylcarbonyl substituent.
- acylamino refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-).
- carbamoyl refers to an amide group attached at the carbonyl carbon atom (i.e., NH 2 -CO-).
- the nitrogen atom of an acylamino or carbamoyl substituent is optionally additionally substituted.
- sulfonamido refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom.
- amino is meant to include NH 2 , alkylamino, arylamino, and cyclic amino groups.
- ureido refers to a substituted or unsubstituted urea moiety.
- a moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent.
- substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluor-3-propylphenyl.
- substituted n-octyls include 2,4 dimethyl-5-ethy-octyl and 3-cyclopentyl-octyl. Included within this definition are methylenes (-CH 2 -) substituted with oxygen to form carbonyl-CO-).
- an "unsubstituted” moiety as defined above e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc. means that moiety as defined above that does not have any of the optional substituents for which the definition of the moiety (above) otherwise provides.
- an "aryl” includes phenyl and phenyl substituted with a halo
- "unsubstituted aryl” does not include phenyl substituted with a halo.
- a suitable aryl amine of general formula 1 can be acylated with a suitable carboxylic acid of general formula 2 to provide compounds of general formula 3 .
- the acylation methods include, but are not limited to, standard peptide coupling reagents, treatment with thionyl chloride or treatment with oxalyl chloride. It will be recognized that compounds of general formula 3 are identical to compounds of Formula I when m is 1.
- Compounds of general formula 3 can be treated with an appropriate reducing agent to provide compounds of general formula 4 .
- Suitable reducing agents include, but are not limited to, lithium aluminum hydride. It will be recognized that compounds of general formula 4 are identical to compounds of Formula I when m is 0.
- Scheme 2 One such alternate synthetic path is described in Scheme 2.
- aryl amine or aryl alcohol of general formula 5 can be reacted with a compound of general formula 6 where LG 1 is a suitable leaving group.
- Suitable leaving groups include, but are not limited to, halo, -OMs, -OTs and the like. It will be recognized that compounds of general formula 7 are identical to compounds of Formula I when m is 0.
- HCMV cytomegalovirus
- HCMV human cytomegalovirus
- Human MRC5 cells were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10 % fetal bovine serum (FBS) and infected with an HCMV variant expressing GFP tagged pUL99 (the product of late viral UL99 gene) at a multiplicity of 1 infectious unit (IU) per cell.
- DMEM Dulbecco's Modified Eagle Medium
- FBS fetal bovine serum
- GFP tagged pUL99 the product of late viral UL99 gene
- Virus yield in the culture supernatant was determined at 96 hours after infection by infecting fresh MRC5 cells and assaying viral IE1 protein expression. Results were plotted using either Prism Software or CDD Vault (CDD Vault was developed by Collaborative Drug Discovery, Inc., 1633 Bayshore Hwy, Suite 342, Burlingame, CA 94010) in order to calculate IC50s.
- antiviral efficacy of some compounds was assessed by inhibition of HCMV replication during in vitro replication assays. Briefly, confluent monolayers of MRC5 fibroblasts in a 96 well plate format ( ⁇ 1.0 ⁇ 10 ⁇ 4 cells/well) were infected with an AD169 strain of HCMV for one hour. After the initial incubation hour, virus containing media was removed and 100ul of media with sequential dilutions of FORGE compounds added to each well. The concentrations of the FORGE compounds were 50 ⁇ M, 25 ⁇ M, 12.5 ⁇ M, 6.25 ⁇ M, 3.125 ⁇ M, 1.56 ⁇ M, and 0.78125 ⁇ M as well as a vehicle control (0.5% DMSO).
- Example Structure HCMV IC 50 Example 1 25 ⁇ M ⁇ IC50 ⁇ 50 ⁇ M Example 2 >50 ⁇ M Example 3 25 ⁇ M ⁇ IC50 ⁇ 50 ⁇ M Example 4 21.2 ⁇ 14.5 ⁇ M Example 5 18.6 ⁇ 4.62 ⁇ M Example 6 21.1 ⁇ 14.5 ⁇ M Example 7 >50 ⁇ M Example 8 3.03 ⁇ 0.69 ⁇ M Example 9 2.41 ⁇ 0.04 ⁇ M Example 10 5.82 ⁇ 1.98 ⁇ M Example 11 5.75 ⁇ 2.47 ⁇ M Example 12 3.34 ⁇ 1.45 ⁇ M Example 13 23.4 ⁇ 0.60 ⁇ M Example 14 2.20 ⁇ 1.32 ⁇ M Example 15 3.27 ⁇ 0.41 ⁇ M Example 16 26.9 ⁇ 11.5 ⁇ M Example 17 2.69 ⁇ 0.94 ⁇ M Example 18
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Claims (13)
- Composé de formule I :- X représente un chaînon symbolisé par NH ou O, sous réserve que si m vaut 1, X représente NH,- R1 et R2 représentent des entités choisies indépendamment parmi un atome d'hydrogène, un atome d'halogène, un groupe alkyle à chaîne droite ou ramifiée, comportant de 1 à 6 atomes de carbone, et un groupe symbolisé par OR6,- R3, R4 et R5 représentent des entités choisies indépendamment parmi un atome d'hydrogène, un atome d'halogène, un groupe cyano, un groupe alkyle à chaîne droite ou ramifiée, comportant de 1 à 6 atomes de carbone, et un groupe symbolisé par OR6,- chaque symbole R6 représente une entité choisie indépendamment parmi un atome d'hydrogène et un groupe alkyle à chaîne droite ou ramifiée, comportant de 1 à 6 atomes de carbone,- l'indice m vaut 0 ou 1,- l'indice n vaut 0, 1, 2 ou 3, sous réserve que si m vaut 1, n ne vaut pas 3,- et Ar représente un groupe de formule- R9 représente une entité choisie parmi un atome d'hydrogène, un groupe alkyle à chaîne droite ou ramifiée, comportant de 1 à 6 atomes de carbone, et un groupe de formule -C(O)R10 ou -SO2R10 où R10 représente une entité choisie parmi les groupes alkyle à chaîne droite ou ramifiée, comportant de 1 à 6 atomes de carbone,ou sel pharmacologiquement admissible d'un tel composé, sous réserve que le composé ne soit pas celui de formule
pour utilisation dans un procédé de traitement ou de prévention d'une infection à HCMV chez un sujet, lequel procédé comporte le fait d'administrer au sujet ledit composé, en une quantité à effet thérapeutique. - Composé pour utilisation conforme à la revendication 1, dans lequel Ar représente un groupe choisi dans l'ensemble constitué par ceux de formules :- R8 représente une entité choisie parmi un atome d'hydrogène, un atome d'halogène et un groupe cyano,- et R9 représente une entité choisie parmi un atome d'hydrogène, un groupe alkyle à chaîne droite ou ramifiée, comportant de 1 à 6 atomes de carbone, et un groupe de formule -C(O)R10 ou -SO2R10 où R10 représente une entité choisie parmi les groupes alkyle à chaîne droite ou ramifiée, comportant de 1 à 6 atomes de carbone.
- Composé pour utilisation conforme à la revendication 2, dans lequel au moins l'un des substituants symbolisés par R3, R4 et R5 se trouve en position ortho et est choisi dans l'ensemble formé par un atome d'halogène, un groupe cyano, un groupe alkyle à chaîne droite ou ramifiée, comportant de 1 à 4 atomes de carbone, et un groupe alcoxy à chaîne droite ou ramifiée, comportant de 1 à 4 atomes de carbone.
- Composé pour utilisation conforme à la revendication 2, dans lequel au moins deux des substituants symbolisés par R3, R4 et R5 se trouvent en position ortho et sont choisis dans l'ensemble formé par un atome d'halogène, un groupe cyano, un groupe alkyle à chaîne droite ou ramifiée, comportant de 1 à 4 atomes de carbone, et un groupe alcoxy à chaîne droite ou ramifiée, comportant de 1 à 4 atomes de carbone.
- Composé pour utilisation conforme à l'une des revendications 2 à 4, dans lequel R2 représente une entité choisie parmi un atome d'halogène, un groupe alkyle à chaîne droite ou ramifiée, comportant de 1 à 6 atomes de carbone, et un groupe symbolisé par OR6.
- Composé de formule I, tel que défini dans l'une des revendications 1 à 6, pour utilisation dans un procédé d'inhibition de la production d'HCMV, comportant le fait de mettre une cellule infectée par HCMV en contact avec une quantité à effet thérapeutique dudit composé.
- Composé pour utilisation conforme à l'une des revendications précédentes, étant entendu que le procédé comporte le fait d'administrer un agent antiviral, en une quantité à effet thérapeutique.
- Composé pour utilisation conforme à la revendication 8, l'agent antiviral étant choisi dans l'ensemble formé par les suivants : acyclovir, docosanol, ribavirine, interférons et similaires, acétate de cellulose, carbopol et carraghénane, pléconaril, amantidine, rimantidine, fomivirsen, zidovudine, lamivudine, zanamivir, oseltamivir, brivudine, abacavir, adéfovir, amprénavir, arbidol, atazanavir, atripla, cidofovir combivir, édoxudine, éfavirenz, emtricitabine, enfuvirtide, entécavir, famciclovir, fosamprénavir, foscarnet, fosfonet, ganciclovir, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, inhibiteur d'intégrase, lopinavir, loviride, mk-0518, maraviroc, moroxydine, nelfinavir, névirapine, nexavir, analogues de nucléotides et/ou nucléosides, oseltamivir, penciclovir, peramivir, podophyllotoxine, rimantadine, ritonavir, saquinavir, stavudine, ténofovir, ténofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, morpholino-oligonucléotides, ribozyme, inhibiteurs de protéase, un inhibiteur d'assemblage, zidovudine, brincidofovir, favipiravir, nitoxanide, létermovir, maribavir, CMX157, ou une combinaison de ceux-ci.
- Composé pour utilisation conforme à la revendication 8, l'agent antiviral étant du ganciclovir.
- Composition pharmaceutique comprenant un composé tel que défini dans la revendication 11 et un véhicule pharmacologiquement admissible.
- Composé conforme à la revendication 11, pour utilisation en tant que médicament.
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US201462077787P | 2014-11-10 | 2014-11-10 | |
PCT/US2015/059763 WO2016077240A2 (fr) | 2014-11-10 | 2015-11-09 | Compositions anti-hcmv et procédés |
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EP3218356A2 EP3218356A2 (fr) | 2017-09-20 |
EP3218356A4 EP3218356A4 (fr) | 2018-05-16 |
EP3218356B1 true EP3218356B1 (fr) | 2022-11-30 |
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EP15859834.2A Active EP3218356B1 (fr) | 2014-11-10 | 2015-11-09 | Compositions anti-hcmv et procédés |
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EP (1) | EP3218356B1 (fr) |
WO (1) | WO2016077240A2 (fr) |
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BR112020007879A2 (pt) | 2017-10-18 | 2020-10-13 | Evrys Bio, Llc | composições antivirais de amplo espectro e métodos |
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US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US5135947A (en) * | 1987-04-09 | 1992-08-04 | Eli Lilly And Company | 1-phenyl-3-naphthalenyloxypropanamines and their use as selective serotonin reuptake inhibitors |
US5858784A (en) | 1991-12-17 | 1999-01-12 | The Regents Of The University Of California | Expression of cloned genes in the lung by aerosol- and liposome-based delivery |
US5292962A (en) * | 1992-12-11 | 1994-03-08 | Eli Lilly And Company | Intermediates to 1-phenyl-3-naphthalenyloxy-propanamines |
US6042820A (en) | 1996-12-20 | 2000-03-28 | Connaught Laboratories Limited | Biodegradable copolymer containing α-hydroxy acid and α-amino acid units |
US6093732A (en) | 1997-12-22 | 2000-07-25 | Pharmacia & Upjohn Company | 4-hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents |
US6472375B1 (en) | 1998-04-16 | 2002-10-29 | John Wayne Cancer Institute | DNA vaccine and methods for its use |
US6248739B1 (en) * | 1999-01-08 | 2001-06-19 | Pharmacia & Upjohn Company | Quinolinecarboxamides as antiviral agents |
CA2468544A1 (fr) | 2001-12-10 | 2003-06-19 | Amgen Inc. | Ligands de recepteur vanilloide et utilisation de ceux-ci dans des traitements |
US20040192728A1 (en) * | 2003-02-03 | 2004-09-30 | Ellen Codd | Quinoline-derived amide modulators of vanilloid VR1 receptor |
JP2010095522A (ja) * | 2008-09-19 | 2010-04-30 | Sumitomo Chemical Co Ltd | 植物病原菌による植物病害を防除又は予防するための農業用組成物 |
US20150335657A1 (en) | 2014-05-05 | 2015-11-26 | The Trustees Of Princeton University | Methods for Modulating Sirtuin Enzymes |
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2020
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US20180170884A1 (en) | 2018-06-21 |
EP3218356A2 (fr) | 2017-09-20 |
US20210040049A1 (en) | 2021-02-11 |
EP3218356A4 (fr) | 2018-05-16 |
WO2016077240A2 (fr) | 2016-05-19 |
WO2016077240A3 (fr) | 2016-08-18 |
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